Peptide YY
Peptide YY (PYY, including the circulating fragment PYY3-36)
Written by Aaron CuhaReviewed Sep 2026
Also known as: PYY, Peptide tyrosine tyrosine, PYY(1-36), PYY(3-36), PYY3-36
A gut hormone released after meals alongside GLP-1. Infused into 12 lean and 12 obese people it cut buffet intake by about 30 percent in both, but the rodent finding it was built on failed a published multi-laboratory replication, and nausea kept it from becoming a drug.
Overview
Peptide YY is a 36 amino acid hormone released from the same intestinal L cells that release GLP-1 and oxyntomodulin, in proportion to the calories in a meal. The enzyme DPP-4 clips two residues off the front to make PYY3-36, which prefers the Y2 receptor, a presynaptic inhibitory receptor on the appetite-driving NPY neurons of the hypothalamus. That DPP-4 switch is the most important mechanistic fact about it: the same enzyme that destroys GLP-1 activates PYY.
The human data are acute infusion studies in small groups, and they are consistent. In the 2003 NEJM crossover trial, 12 obese and 12 lean participants received PYY3-36 or saline by infusion; calorie intake at a buffet lunch two hours later fell 30 percent in the obese group and 31 percent in the lean group, both p less than 0.001, and cumulative 24-hour intake also fell. Obese participants had lower fasting PYY (10.2 versus 16.9 pmol/L) and were not resistant to it, which is the contrast with leptin that made the paper matter. Later crossover studies from the same London group found PYY3-36 plus oxyntomodulin cut intake by 42.7 percent in 12 overweight or obese volunteers, more than either alone, and a 10.5-hour subcutaneous infusion of GLP-1, oxyntomodulin and PYY at post-bypass levels cut intake by 32 percent.
The rodent literature is where the dispute lives. The 2002 Nature paper reported that peripheral PYY3-36 reduced food intake and weight gain in rats and mice and, in a human arm, cut intake by 33 percent over 24 hours. In 2004 Nature published a Brief Communication from investigators across several independent laboratories reporting that they had been unable to replicate the rodent food-intake effect. Both sides are set out below; the human infusion effect has been reproduced, the rodent effect is contested, and neither result should be used to dismiss the other.
No PYY-based drug is approved anywhere. Every human study measured energy intake over hours, not body weight over months and not clinical outcomes, and nausea was dose-limiting. Native PYY3-36 is sold by research chemical suppliers and is not approved for any use.
Mechanism of action
Established in humans by infusion: PYY3-36 at postprandial concentrations reduces appetite ratings and ad libitum energy intake for hours, lowers plasma ghrelin, and does so equally in lean and obese people. Established in rodents but contested (see the dispute): peripheral PYY3-36 reduces food intake through the Y2 receptor, an effect absent in Y2 receptor knockout mice, with increased c-Fos in the arcuate nucleus, reduced hypothalamic NPY mRNA and inhibition of NPY neuron firing that disinhibits adjacent POMC neurons. PYY(1-36) is relatively non-selective across Y1, Y2 and Y5 receptors; DPP-4 cleavage to PYY3-36 confers Y2 preference. PYY also slows gastric emptying and intestinal transit, the older ileal brake function.
Human evidence
Several small randomised placebo-controlled crossover infusion studies, all measuring energy intake over hours. The acute effect on food intake has been reproduced, alone and in combination with GLP-1 and oxyntomodulin. No study has measured body weight over months, and no trial has tested a PYY product for any clinical outcome.
- NEJM 2003: 12 obese and 12 lean participants, crossover. Buffet intake down 30 percent (obese) and 31 percent (lean) two hours after infusion; 24-hour intake also down; ghrelin reduced. Obese participants had lower fasting PYY and normal responsiveness.
- Nature 2002, human arm: infusion at normal postprandial concentrations reduced appetite and cut 24-hour intake by 33 percent.
- Diabetes 2010: 12 overweight or obese volunteers, PYY3-36 plus oxyntomodulin cut test meal intake 42.7 percent, more than either alone.
- JCEM 2017: obese volunteers, 10.5-hour subcutaneous GLP-1 plus oxyntomodulin plus PYY infusion at post-bypass levels cut intake 32 percent, energy expenditure unchanged.
- ClinicalTrials.gov, searched 11 September 2026: PYY appears in dozens of registered studies as a measured hormone; no interventional trial of a PYY product was returned under that term.
What this does not tell you: All of this is acute: one infusion, one meal, at most a day. Nothing shows that PYY3-36 lowers body weight over weeks, that the effect survives repeated dosing, or that it changes any health outcome. Nausea is the recognised dose-limiting effect and the studies used concentrations at or near the physiological range. The largest study has 24 participants and most come from a single London research group. Native PYY3-36 has a short half-life and there is no published pharmacokinetic basis for the way research-chemical buyers use it.
Reading the research record
PYY has a reputation problem that GLP-1 does not, and the reason is a specific published event. The 2002 Nature paper reported that peripheral PYY3-36 reduced food intake and weight gain in rodents and reduced intake in humans. In 2004 Nature published a Brief Communication from investigators across a number of independent laboratories who reported that they had been unable to reproduce the rodent food-intake effect, stated that the reasons for the discrepancy were undetermined, and argued that an anti-obesity approach whose foundational finding could not easily be replicated was of questionable value. The original authors and others attributed the failures to stress and acclimatisation in the animals, since PYY3-36's effect is small and stress itself suppresses feeding; the replicating groups did not accept that the effect should be so fragile. That exchange has not been formally resolved and we do not resolve it. The rodent effect is contested, full stop.
The human effect is a separate question and it has held up: the 2003 NEJM crossover, the 2010 combination crossover and the 2017 triple-hormone infusion all found meaningful reductions in energy intake, from three different protocols. What nobody has done is turn that into a drug. Native PYY3-36 causes nausea at doses that suppress intake, has a short half-life, and as an endogenous sequence attracts no patent protection, so the acute studies were never followed by a weight-loss trial of the native peptide. The pharmaceutical interest moved to engineered long-acting Y2 agonists and to combining PYY activity with GLP-1 agonism, which is why PYY matters to this site chiefly as a ligand: the L cell co-secretes it with GLP-1 and oxyntomodulin, and the combination infusions are the physiological argument behind multi-hormone obesity drugs.
The evidence, charted
Fig. 1 · evidence composition
3of 8 citations (38%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 7 distinct years, 2002 to 2017, counted from the citation list on this page. The newest citation on file is from 2017, more than five years ago; the published record may have gone quiet.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Not approved
CA
Not approved
Approved in 1 of 4, prescription route in 0, not approved in 3. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2003
Inhibition of food intake in obese subjects by peptide YY3-36
12 obese and 12 lean participants, double-blind placebo-controlled crossover. Buffet lunch intake two hours after PYY3-36 infusion fell 30 percent in obese and 31 percent in lean participants (both p < 0.001); cumulative 24-hour intake also fell; ghrelin fell. Fasting PYY was 10.2 pmol/L in obese versus 16.9 in lean (p < 0.001) and correlated inversely with BMI (r -0.84). Non-US government funded.
New England Journal of Medicine - Animal2002
Gut hormone PYY(3-36) physiologically inhibits food intake
Peripheral PYY3-36 inhibited food intake and reduced weight gain in rats, and inhibited intake in wild-type but not Y2 receptor knockout mice, with arcuate c-Fos induction and reduced hypothalamic NPY mRNA. A human arm reported that infusion at postprandial concentrations cut intake by 33 percent over 24 hours. The rodent arm is the one that failed replication.
Nature - Animal2004
Physiology: does gut hormone PYY3-36 decrease food intake in rodents?
A Brief Communication from investigators at several independent laboratories reporting that they had been unable to replicate the rodent food-intake and weight-gain findings of the 2002 paper, stating the reasons for the discrepancy were undetermined and questioning the value of PYY3-36 as an anti-obesity approach on that basis.
Nature - Human2010
PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans
12 overweight or obese volunteers, randomised double-blind placebo-controlled crossover. Energy intake at a test meal during combined PYY3-36 and oxyntomodulin infusion was 42.7 percent below saline and significantly below either hormone alone. Non-US government funded.
Diabetes - Human2017
The Effect of a Subcutaneous Infusion of GLP-1, OXM, and PYY on Energy Intake and Expenditure in Obese Volunteers
Single-blind randomised placebo-controlled crossover in obese volunteers: a 10.5-hour ambulatory subcutaneous infusion of GLP-1, oxyntomodulin and PYY at doses matching post-gastric-bypass levels (PYY 0.4 pmol/kg/min) cut food intake by a mean 32 percent with no change in resting energy expenditure. Non-US government funded.
Journal of Clinical Endocrinology and Metabolism - Review2017
Ghrelin, CCK, GLP-1, and PYY(3-36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB
Comprehensive physiological review of PYY3-36 secretion and action in health, obesity and after bypass surgery, including the assessment that its physiological satiation role in humans is less securely established than that of GLP-1.
Physiological Reviews - Review2015
PYY3-36: Beyond food intake
Review of PYY3-36 actions beyond appetite, including gut motility, energy expenditure and bone, most of it from animal work.
Frontiers in Neuroendocrinology - Review2008
The role of PYY in feeding regulation
Review written in the middle of the replication dispute, covering the receptor pharmacology and the discordant rodent data.
Regulatory Peptides
Frequently asked questions
Does PYY3-36 reduce appetite in humans?
Acutely, yes, in several small crossover trials. Infused into 12 lean and 12 obese people it cut buffet intake by about 30 percent two hours later and reduced 24-hour intake. Combined with oxyntomodulin it cut intake by 42.7 percent in 12 volunteers. No study has measured weight over months.
What is the PYY replication controversy?
The 2002 Nature paper found PYY3-36 reduced food intake in rats and mice. In 2004 investigators from several independent laboratories reported in Nature that they could not reproduce that rodent effect. The dispute concerns the rodent data; the human infusion effect has been reproduced in later studies. Neither finding cancels the other.
Are obese people resistant to PYY the way they are to leptin?
Not in the 2003 trial. Obese participants had lower fasting PYY (10.2 versus 16.9 pmol/L in lean participants) and responded to infused PYY3-36 with the same 30 percent reduction in intake. That was the paper's central point.
Why is there no PYY drug?
Nausea at effective doses, a short half-life, and no patent on the natural sequence. The acute studies were never followed by a weight-loss trial of native PYY3-36. Drug development moved to engineered long-acting Y2 receptor agonists and to combinations with GLP-1 drugs, which remain investigational. No PYY-based product is approved anywhere.